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PSMA-PET Imaging:  Finding the Needles in the Haystack

We’ve talked about PSMA-PET before, but now it has gotten FDA approval for use in imaging prostate cancer.  This is just the start: more approvals are expected.  PSMA-targeting is also being used in Europe and Australia, and in clinical trials in the U.S., as a means of treating prostate cancer, not just showing where it’s hiding in the body.  For the Prostate Cancer Foundation (PCF), I recently interviewed Thomas Hope, M.D., part of a team of scientists at UCSF and UCLA whose PCF-funded research led to the FDA approval for PSMA-PET imaging.  The possibilities here are truly exciting:

“If we can see it on PSMA-PET, we can treat it, right?”

 “My PSA is no longer undetectable after surgery, but cancer didn’t show up on a PSMA-PET scan.  Do I still need radiation therapy?”

 “I’m at high risk of cancer recurrence.  A bone scan was negative, but the PSMA-PET scan shows a few spots of cancer outside the prostate.  Do I have metastatic prostate cancer?”

 These are just some of many new questions that men with prostate cancer and their doctors are starting to deal with after recent FDA approval of PSMA-PET, a new kind of scan that can show, for the first time, the needles in the haystack – tiny spots of prostate cancer hiding in the body that are too small to be picked up by standard imaging.

PSMA stands for prostate-specific membrane antigen, a molecule identified in the late 1980s that sits on the surface of prostate cancer cells.  Supported by many years of PCF funding, scientists have managed to link PSMA to radioactive tracers that can home in on this very specific molecule wherever it happens to be:  think of heat-seeking missiles locking onto a target.  Depending on the radioactive molecule linked to PSMA, it can either detect prostate cancer by shining a virtual spotlight on areas as small as a BB – the imaging technique the FDA has just approved – or detonate it with chemotherapy or tiny doses of radiation delivered by radionuclides at the cellular level.  In Europe and Australia, and in clinical trials in the U.S., PSMA-PET is being used to target and kill cancer in just those tiny outposts, leaving nearby cells unscathed.

“The PCF saw the potential of PSMA targeting way back in 1993,” says medical oncologist and molecular biologist Jonathan Simons, M.D., CEO of PCF.  “Over nearly 30 years, we have invested more than $26 million in research on PSMA, with the goal of finding cancer that has escaped the prostate when it is very early and at a very small volume, because we believe that the sooner we can target it, the sooner we will be able to treat it and change the course of metastatic prostate cancer.”

The particular PSMA-targeted contrast agent that just got approved – a remarkable achievement in itself, based on five years of research by investigators Thomas Hope, M.D., at the University of California-San Francisco, and Johannes Czernin, M.D., and Jeremie Calais, M.D., MSc., at the University of California-Los Angeles – is called 68Ga-PSMA-11.  (The “Ga” stands for gallium; other PSMA agents are in various stages of getting FDA approval.)  And this particular FDA approval, for now, is for use on a very small scale:  only in California, at UCSF and UCLA.  But it’s a start – and it marks an important milestone in prostate cancer detection and treatment.  

This FDA approval is for use of PSMA-PET imaging in two main groups of patients (for now), says Hope, who is Director of Molecular Therapy in the Department of Radiology and Biomedical Imaging at UCSF: “in high-risk men before treatment with prostatectomy or radiation therapy, and in men who have already been treated for localized prostate cancer who have a rising PSA.”

The strong collaboration among the PCF-funded scientists at UCLA and UCSF undoubtedly helped secure the FDA’s approval – itself a bit of a milestone.  “This is really unusual,” Hope notes.  “The FDA has never approved a drug at two manufacturing centers before, and both centers were approved on the same day.”

Achieving a PSMA-PET scan is more labor-intensive and expensive than patients might realize, Hope adds.  “We have to make the imaging agent ourselves in small batches,” a high-tech process that requires a gallium generator, and the solution can’t be stockpiled for long-term storage, because gallium has a half-life of a little more than an hour.  “For now, there is no commercially available PSMA-PET contrast agent,” but Hope believes this will change soon; two new drug applications for PSMA agents are under review by the FDA, and more are expected.

Note:  Many men won’t ever need PSMA-PET.  If you have a small amount of Gleason 6 prostate cancer and you are enrolled in active surveillance, or you were diagnosed with low- or intermediate-risk cancer that was treated with surgery or radiation and your PSA is undetectable, then PSMA-PET is probably not something you will need to consider.  But for other men – those with a rising PSA after treatment, for instance; men at high risk of cancer recurrence; or some men with metastatic prostate cancer – PSMA-PET can help determine what to do next.  As Hope says, “Now we know where it is.  The question then becomes, what’s the best way to treat it?”

Smarter Treatment

Having this extra insight shouldn’t be a scary prospect, he adds.  “It’s never bad to know; instead, what can we do with this knowledge?” One exciting thing is to treat men with oligometastasis, as oncologist Phuoc Tran, M.D., Ph.D., is doing at Johns Hopkins: and he’s going after a cure!   Another thing is to actually put the treatment where the cancer is, instead of where it is not.  Hope explains:  Many men who have a rising PSA after prostatectomy “get radiation therapy blindly to the prostate bed; 30 percent of those patients have a recurrence of cancer after about two years.  But with PSMA-PET, we know that about 30 percent of these patients have disease outside the radiation field.  Those are the patients who are recurring!  Now we can expand the radiation field to include known sites of cancer.  We assume the patient will benefit – we just haven’t proven it yet.  Do we not want to know where the disease is, and treat them blindly?” No! And this could be a game-changer for some men.

It’s also important to note that PSMA-PET is not the perfect crystal ball; it can’t detect areas of cancer that are really tiny.  Hope says that “some patients take a negative PSMA-PET to mean they don’t need any treatment,” and that’s not always correct.  “If you have biochemical recurrence (a rising PSA), and PSMA-PET doesn’t show any evidence of disease, the cancer is going to continue to progress.  Don’t think you don’t need treatment, particularly if you’re a candidate for salvage radiation therapy.”

These and other issues will become increasingly clear as PSMA-PET becomes incorporated into the standard of care.  As Hope notes, “It’s early days yet.”

In addition to the book, I have written about this story and much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

 ©Janet Farrar Worthington

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A Power Outage for Prostate Cancer

Limiting Prostate Cancer’s Fuel by Restricting Calories and Changing the Diet:  Just when it seems like the picture of diet and prostate cancer is finally coming into focus, Nicole Simone, M.D., a radiation oncologist at Thomas Jefferson University, has added a new dimension.  It may not be just a question of the good foods you do eat, and the bad foods you don’t eat:  It also appears to matter, very strongly, how much you eat at all.

Simone’s research in prostate cancer and also in breast cancer suggests that restricting calories has many anti-cancer effects in the body – including, in mice, decreasing the likelihood of metastasis.  Early research in humans has shown, so far, that it lowers inflammation, changes the gut microbiome, may decrease the side effects of systemic therapy and generally seems to slow down cancer.  In effect, caloric restriction gives cancer a “brown-out,” limiting its energy.  “We’re just beginning to understand the promise and the power of caloric restriction,” says medical oncologist and molecular biologist Jonathan Simons, M.D., CEO of the Prostate Cancer Foundation (PCF), which funded this research.  “If there were a drug that could do all these things, we’d prescribe it in a heartbeat.”

Wait… aren’t people with cancer supposed to keep their calories up?  If you’re thinking that limiting calories when someone’s fighting cancer seems like the opposite of the common wisdom – well, you’re right!  “This is not what we were all taught in medical school,” says Simone.  And she’s not entirely sure why this approach produces as many good effects as it does – but here’s a clue:  One way to look for various forms of cancer is with a PET scan, which involves injecting a radioactive dye.  “That dye is actually a radio-labeled glucose,” which is eagerly taken up by tumor cells because “cancer loves to eat.  Cancer is metabolically active, and sugar is one of its favorite foods!”

Simone’s laboratory has been investigating caloric restriction for several years.  “Initially, we were looking for a way to increase the effectiveness of radiation and chemotherapy in tumors that have a poor response to standard therapies.”  In mouse models of hormone-sensitive breast cancer, Simone found that simply restricting the mice’s daily caloric intake made a big difference:  it not only altered cell metabolism and made cancer cells more vulnerable to radiation and chemotherapy.  It also “decreased metastasis and increased overall survival.”

If this worked in breast cancer, would it work in prostate cancer?  Yes!  “In several models of hormone-sensitive prostate cancer, we found the same,” she says.  “We were able to decrease tumor growth, decrease metastasis, and increase survival.”  Then Simone’s lab tested caloric restriction in mice with castrate-resistant prostate cancer (CRPC), cancer that is no longer controlled by androgen deprivation therapy (ADT).  Again, caloric restriction affected how tumors responded to radiation.  “We saw some really interesting systemic, molecular changes,” Simone says.  “We wanted to take it a step further, and use that preliminary data as a launching pad to see what would happen in patients with prostate cancer if we put them on a caloric restriction diet.”

Eating 25 percent less:  In a pilot study, 20 patients – men diagnosed with localized prostate cancer who were scheduled to have prostatectomy – underwent caloric restriction for 21 days.  Simone individually tailored each man’s daily calorie total, based on what he had reported eating for several days ahead of time.  “We figured out their average caloric intake and then decreased that by 25 percent.”  Simone’s team also gave the men some dietary guidelines, encouraging (but not requiring) an anti-inflammatory diet with less refined sugar and processed food, more fruits, vegetables and complex carbohydrates.  “The men were able to stick to the diets really nicely,” she says.  “We went over their diet logs and calculated their dietary inflammatory index.   They did increase their anti-inflammatory foods!  They also lost an average of 12 pounds each.”

Could just three weeks of restricted-calorie, pretty much anti-inflammatory diet make a difference?  Yes, in several ways:

A decrease in systemic inflammation.  Men had changes in inflammatory markers in the blood, including a lower sedimentation rate (a blood test that measures inflammation).

Changes in the gut microbiome.  Rectal swabs, taken before the men started the diet and three weeks later, were sent to PCF-funded investigator Karen Sfanos, Ph.D., at Johns Hopkins, who performed in-depth analysis.  In the swabs taken at three weeks, Sfanos found a significant change in what the gut microbes were producing:  more butyrate!  Butyrate is an important fatty acid that helps control inflammation and is made by beneficial bacteria.  The fact that butyrate increased suggests that the population of bacteria in the gut changed for the better, simply with caloric restriction and an anti-inflammatory diet.

Less inflammation in the gut wall, as measured by lipopolysaccharides (LPS) in the blood.  “When there is inflammation in the gut, it creates spaces between the epithelial cells in the gut wall.”  Inflammatory cells can “leak” out of the gut into the blood, and increase inflammation elsewhere.

Less inflammation in the tumor.  “We saw a decrease in inflammatory markers such as NF-κB (an inflammatory pathway) in the tumor itself, and in MIR21.”  MIR21 is a microRNA gene (which makes RNA instead of proteins) that is believed to drive cancer development, growth, metastasis, and resistance to treatments.  Simone is discussing this aspect with another scientist she met at PCF’s Scientific Retreat, Shawn Lupold, Ph.D., of Johns Hopkins, who is a pioneer in the study of MIR21.

Ultimately, Simone believes, caloric restriction can play an important role for men with all stages of prostate cancer – but to make it even more effective will also require precision nutrition, based on precision oncology.  In this case, that means figuring out whether someone’s cancer prefers a diet that is sweet or savory.  “Prostate cancer can metabolize through the glucose pathway, or through lipid pathways,” says Simone.  Understanding which pathway really appeals to a particular cancer – some prefer sugar, some really go for fat– “can tell us how your cancer is driving its own energy.”

Thus, “if the tumor’s feeding on lipids, we change the dial on fat content in the diet.”  And if the tumor prefers sugar, then a diet aimed at keeping sweets and simple carbohydrates to a minimum will foil the cancer’s gustatory pleasure.

One of the biggest challenges with chemotherapy, ADT, or even radiation therapy, is resistance to treatment:  the cancer evolves to minimize the damage of attempts to kill it.  “Diet can almost be a more powerful tool,” says Simone.  “Cancers get smarter; a drug will work well for a while, then all of a sudden, cancer will figure out a way around it.  The power of restricting food is that it provides less energy for the cancer to use up.”

In addition to the book, I have written much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

 ©Janet Farrar Worthington

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Worried About Prostate Cancer?  Be Proactive! Part 2: Exercise and Key Foods

Recently for the Prostate Cancer Foundation (PCF), I interviewed two scientists who study lifestyle factors and their effect on prostate cancer:  Epidemiologist June Chan, Sc.D., of UCSF, and epidemiologist Lorelei Mucci, M.P.H., Sc.D., of Harvard.  In the last post, we talked about diet.  Now let’s look at exercise, and we’ll wrap up with some quick takes on various foods.

Here’s some good news:  By launching your proactive strike against prostate cancer, you’re not just helping your prostate (or helping to keep cancer from coming back, if your prostate is long gone):  You’re helping your heart, and you’re also helping to lower the risk of diabetes and insulin resistance.  Go, you!

A sedentary life is not good for the heart.  Diet is important, but it’s not the whole story here.  The research team of June Chan at UCSF has shown in multiple studies that exercise can help delay or prevent prostate cancer progression.  “Aerobic exercise after prostate cancer diagnosis may reduce the risk of prostate cancer recurrence or death by 60 percent.”  Chan’s earlier studies in this field, funded by PCF nearly a decade ago, showed a benefit to an hour of jogging six days a week – the level of exercise most of us can’t or don’t want to sustain.  But don’t get discouraged!  In more recent studies, she and colleagues have been looking at more doable levels of exercise – walking 30 minutes a day, or three or more hours a week, at a brisk pace (3 mph or faster).  The brisk pace is important:  One study found that men who walked three or more hours a week after diagnosis had a 57-percent lower risk of having prostate cancer recur than men who walked at a slower pace, for less than three hours a week.

“Just walking, not running!  Walking is so common.  During these Covid times, when we’re confined to small spaces, people might find it difficult to walk the way they would prefer,” says Chan.  “But I would say, just use it as a break to get fresh air – even if you’re just going up and down the same block.  Any little bit of walking, as opposed to sitting.  Movement is good for your overall bone health.  Don’t push yourself to injury; just get in a good habit.  It’s something you can do when you’re doing something else;” for example, “when I’m walking, often I’ll grab my phone, and use it as a chance to catch up with somebody.”  Don’t focus on the number of steps, or the time.  “If you’re always looking at your watch, you’re not enjoying the walk as much.”  And don’t overdo it:  “If you get injured, you might lose all interest in continuing.”

Note:  the key here is giving the cardiovascular system a good workout, not necessarily the act of walking itself.  So, apply this to your own needs:  if walking that much is not a good option for you, swimming and riding an exercise bike – whatever you are able to do – are good, too.  Studies by Chan and others have provided so much proof of the benefit of aerobic activity, in fact, that “we’re actually at the stage now that the updated Physical Activity Guidelines put out by the American College of Sports Medicine specifically note that exercise is recommended for men with prostate cancer to avoid the risk of dying from prostate cancer.  We’re really excited that we got to contribute to that work.”

What is it about exercise?  Chan and colleagues are still tapping the surface of all the ways exercise is good for the body.  “It improves energy metabolism, lowers inflammation and oxidative stress, helps boost immunity, and is beneficial for androgen signaling pathways.”  It is good for the heart and lungs, improves muscle strength and muscle mass, burns fat, lowers fatigue, anxiety, stress, and depression.  “It just improves your overall quality of life,” says Chan.  Bonus:  exercise also may help slow down prostate cancer’s growth.

Chan is investigating the underlying biological mechanisms for “why exercise has these benefits for prostate cancer and overall health.  Is it a systemic effect, or an anti-androgenic effect?  Is it acting on oxidative stress pathways?”  Her group is looking for insight from blood and tissue samples taken from men with prostate cancer before and after exercise interventions.  In another large, phase 3 clinical trial funded by Movember, Chan and epidemiologists Stacey Kenfield and Lorelei Mucci, with principal investigators Rob Newton and Fred Saad, are studying high-intensity exercise in men with metastatic prostate cancer, at more than a dozen sites worldwide. “It’s a two-year, tailored intervention, with both strength and aerobic components,” to see if exercise can help men with metastatic prostate cancer live longer and better.  What else lowers stress?  Meditation.  Stress may play a role in the growth of prostate cancer, so lowering stress is a strategy worth pursuing.

Speaking of strength training:  We all lose muscle mass as we get older.  Strength training (lifting weights or using resistance bands, and doing muscle-building exercises) fights this loss.  Strength training can be especially helpful in men on androgen deprivation therapy (ADT) for advanced prostate cancer, who are at higher risk of loss of muscle mass, osteoporosis, and also of weight gain, metabolic syndrome, and diabetes.  Note:  If you have advanced prostate cancer, check with your doctor to make sure strength training is safe, and also for some guidance about the weights you should be lifting.

Final note on exercise:  Start out slow.  “If you have not exercised regularly for a long time, consult with a physician or personal trainer, to get a program tailored to fit you,” says Chan.  “Start small, and go up by five- or ten-minute increments.  Then see if you can pick up the intensity.  Just make little changes.”

Look to the long haul:  “Thank goodness I ate that broccoli on Thursday.  Now I won’t get prostate cancer,” said no one ever.  It’s not just one good food choice, but many years of erring on the side of healthy.  The other side of that, however, is reassuring:  It’s not just one bad food choice, or being a couch potato last weekend, but many years of not eating things that can help your body fight prostate cancer, many years of not exercising.  “Diet is something you have to do every day,” says Chan.  So is exercise.  That said, “we’re all balancing so many things with food.  Food is part of our culture, taste, our family habits, celebrations.  I feel like the recommendations should just be like filters.”  In other words: many good decisions, over time, will help fight prostate cancer more than the occasional lapse will help promote it.

 

Thumbs Up, Thumbs Down:  Quick Takes on Food

            I asked Lorelei Mucci for her expert opinion on some foods you may be wondering about for their cancer-fighting powers.  Here’s the rundown, in no particular order:

Extra virgin olive oil (EVOO):  Yes!  More than 2 tablespoons a day.  Among other things, EVOO contains hydroxytyrosol, which scientists now recognize as a natural means of cancer chemoprevention.  It is a powerful antioxidant, and it has been shown to protect against cancer by slowing proliferation of tumor cells and increasing apoptosis – “suicide” – of cancer cells.

Tomatoes:  Yes!  Especially when cooked in, or drizzled with, olive oil, which helps you absorb a key component of tomatoes, lycopene.  “The prostate accumulates a lot of things,” including cholesterol.  “It accumulates lycopene.  When a man eats a diet high in lycopene, for some reason, lycopene levels in the prostate go up.  Lycopene makes sense biologically, because it does accumulate in the prostate.  It is an antioxidant.  This is one of the individual dietary components that seems pretty promising.”

Don’t like tomatoes?  Good news:  Lycopene is in watermelon and grapefruit, too!

Coffee:  “Coffee is looking more and more promising .  There are now a number of studies that suggest drinking coffee regularly, one to two cups a day, can help prevent aggressive forms of prostate cancer.  Some studies say three to four cups offer even more of a benefit, but there’s an initial benefit with one to two cups.  Coffee may also lower the risk of diabetes, liver cancer, and Parkinson’s disease.”

Tea:  Sure, what the heck.  There are far fewer studies on tea than on coffee, but tea has antioxidants.  People in Asia, which has less prostate cancer than the U.S., drink a lot of green tea.  “Tea lowers inflammation, but has not been shown to have an effect on insulin levels.”  However, and this is important:  it doesn’t seem to raise your risk of getting prostate cancer.

Note:  If you go to a fancy coffee shop and get a 1,500-calorie coffee with not only cream but whipped cream, and loads of sugar, or if you drink a super-sweet tea loaded with sugar or high fructose corn syrup, the effects on insulin resistance and risk of weight gain will probably cancel out the antioxidants.

Fish:  Yes.  “We published a meta-analysis of epidemiologic studies that looked at fish and prostate cancer death, and there was a pretty good benefit with regular consumption of fish.”  Particularly “dark-meat” fish rich in omega-3 fatty acids, like salmon and red snapper.

Devil’s advocate:  Are men healthier because they eat fish, or because if they choose fish, they’re not eating a big old ribeye steak cooked in butter?  Talk amongst yourselves, but fish is not nearly as pro-inflammatory as red meat.

Nuts:  Sure.  “There’s not much evidence one way or another with prostate cancer death, but they really seem to lower the risk of cardiovascular disease and overall mortality.”  Also, if you’re eating a handful of nuts as a snack, maybe you won’t be eating a bag of chips.  “In one of our studies,” says June Chan, “we observed that substituting 10 percent of calories from carbohydrates for calories from healthy, plant-based fat (nuts) was associated with a 29-percent lower risk of prostate cancer death, and a 26-percent lower risk of all-cause death.”

Pasta:  In moderation.  However, non-traditional pastas, made from cauliflower or chick peas, are another way to sneak in vegetables.  They may also help you manage your weight.  “Excess body weight, particularly the visceral fat around the abdomen, is associated with worse outcomes from prostate cancer.  Anything men can do to help reduce their weight – limiting bread and pasta, and increasing things like cauliflower pasta and vegetable intake – is beneficial.”

Charred meat:  Try to limit it.  When food is charred, it makes a chemical compound called PhIP, that is a known carcinogen.   Even worse: those beautiful (charred) grill marks combined with a pro-inflammatory food, like red or processed meat.

Soy:  sure.  “Consumption of soy is much higher in Asia, where the incidence of prostate cancer death is lower.  Soy is probably part of a strategy for maintaining healthy weight, and it’s a way of replacing red meat.  Does it lower prostate cancer death?  I don’t know that we have that evidence.”  Another complicating factor:  “Men who eat more healthy diets tend to get screened for prostate cancer.  If you get regular PSA testing, you’re five times more likely to get diagnosed with prostate cancer.”  And, if you get diagnosed early, you are more likely to get early treatment while the disease is confined to the prostate.  It’s like the children’s book, If You Give a Mouse a Cookie, a domino effect.

Vitamin D:  Yes.  “There’s really promising data on vitamin D and prostate cancer mortality.”  One randomized trial, the VITAL study, showed “specifically in black men who have low levels of vitamin D, there’s a reduction in prostate cancer mortality.  Evidence from many studies suggests that this makes sense; there’s a lot of genetic data on inherited vitamin D pathways; this pathway seems to be very important for prostate cancer.”  Vitamin D is found in some foods, such as fatty fish and egg yolks, and your body makes vitamin D when you get out in the sunlight.  However, most people don’t have sufficient levels of vitamin D.  Thus, your best strategy is to take a vitamin D3 supplement:  2,000 IU daily.  It’s not a case of “more is better.”  2,000 IU is what you need.

Final thought on food:  In the words of the title song on Al Jarreau’s 1977 breakthrough album:  Look to the Rainbow.  Build your diet around an array of colorful, plant-based fruits and vegetables: green, red, yellow, orange and purple.  Those colors reflect the good nutrients in them.  Eat less red meat, and have restraint with sugar and carbs, and go for EVOO instead of butter.

In addition to the book, I have written much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

 ©Janet Farrar Worthington

 

 

 

 

 

 

 

 

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Worried About Prostate Cancer?  Be Proactive! Part One

Part One:  Live Your Best Life!

What can you do to live your best life?  You might say, quite reasonably, that your best life does not include prostate cancer.  True.  But no matter where you are in your journey – prevention, treatment, recovery, or survivorship – what can you do to maximize the good, to help your physical and mental wellbeing?  There’s actually quite a lot!

For example: Exercise not only helps you lose weight; it helps fight depression, and it even can help slow down prostate cancer!  And eating the right diet – as opposed to eating a lot of junk and chemicals – can boost your spirits, your energy level, and just generally make you feel better.  Even better:  it can help lower inflammation and insulin, and this can help your body fight prostate cancer, and can help prevent diabetes, cardiovascular disease, and other chronic illnesses.

There is growing evidence that the lifestyle choices that help prevent or fight other diseases – like, eating low sugar for diabetes, or exercising for your heart – can also help prevent or slow down prostate cancer.

Here are three basic principles:

What lowers inflammation helps fight prostate cancer.

What fights diabetes and insulin resistance helps fight prostate cancer.

What is good for the heart is good for the prostate.  We will cover all of this here and in part two.

Studying Diet is Hard

For the Prostate Cancer Foundation (PCF), I interviewed two scientists who study lifestyle factors and their effect on prostate cancer:  Epidemiologist June Chan, Sc.D., of UCSF, and epidemiologist Lorelei Mucci, M.P.H., Sc.D., of Harvard.

Right off the bat, both of these experts note that studying food is hard, and the answer to staying healthier is not one single thing.  There is no dietary magic bullet, and if you see one advertised and choose to take it, do so with a huge proverbial grain of salt!  In many studies over the years, scientists have tried to isolate specific foods to see if they promote or prevent cancer – but they did it by asking people to recall what they ate over certain periods of time.  And most people don’t have ideal memories:  “Yes, I ate that fairly regularly.  No, I didn’t eat this – wait, maybe I did.”  See the difficulty?

Okay, so what if people keep a food journal?  That’s more helpful, although these kinds of studies, done right, take many years.  Even then, if you isolate certain foods that seem promising, you still don’t know exactly what’s happening!  Let’s say you are studying what people eat and you notice a trend in those who didn’t get cancer:  they eat apples (hypothetically).  What kind of apples?  Is it all apples, or just Granny Smiths?  Were they all grown in the same type of soil?  Were they cooked, or eaten raw?  Peeled or not?  Organic or not?  How many did people eat a day?

But wait!  Did these people even have an actual benefit from eating the apple – say, one they brought to work from home – or did they benefit from not eating a bag of cheese puffs or Twinkies from the vending machine instead?

And wait some more!  Do the people who benefited have genetic or molecular differences that make them more likely to be helped by apples?  Or… are people who eat apples also more likely to exercise and take better care of their health in general – so maybe it’s not even the apples but their whole lifestyle that made the difference, and we’re back to the drawing board!

This is why science around nutrition takes time.  Remember back in 2010 when coffee was bad?  And now, here we are in 2020 and coffee is good?  This stuff evolves.  The good news is, we’ve learned a lot.

Broad Strokes are Better

Scientists don’t have a Paint-by-Number approach to food science, with every single food accounted for.  But they are able to paint with broad, but definitive, strokes.

In our interviews, June Chan and Lorelei Mucci both cited work led by Harvard scientists Fred Tabung, Ph.D., M.S.P.H., and Edward Giovannucci, M.D., Sc.D., that look at the relationship between diet and inflammation.  In one, the scientists tracked inflammatory markers in the blood and whether inflammation was raised or lowered by what people ate, based on data from thousands of participants in the Nurses’ Health Study and the Health Professionals Follow-Up Study.  The key for us is the foods they found that reduce inflammation:  dark yellow vegetables (carrots, winter squash, sweet potatoes, etc.); leafy green vegetables (like spinach, broccoli, kale, etc.), coffee, and wine.  Beer (one bottle, glass, or can) was in this category, too.  So was tea, but its effect was not very strong.

The pro-inflammatory (bad) category, included processed meats (hot dogs, bacon, pepperoni, lunch meat, etc.), red meat, refined grains, high-energy beverages (with additives and sweeteners), and “other vegetables,” like potatoes and corn.  Interestingly, not all fish is equal:  canned tuna, shrimp, lobster, scallops, and “other” fish were more inflammatory than “dark-meat” fish like salmon or red snapper.

But if you love canned tuna, and if you love a baked potato or corn on the cob, don’t freak out:  remember, broad strokes!  The key seems to be to make sure you do eat the anti-inflammatory foods.  For example, the anti-inflammatory effects of leafy green vegetables, dark yellow vegetables, wine and coffee are more powerful than the very mild, pro-inflammatory effect of “other fish” or “other vegetables.”  If you feel that you just can’t give up meat entirely, that’s okay – just aim for smaller portions of meat, surrounded by anti-inflammatory vegetables.  Example:  instead of regular fries, try sweet potato fries.  They’re really good, and they fight inflammation!  You can have your burger, but still help counteract inflammation:  it’s a win-win!

So:  what about foods that are bad for diabetes and insulin resistance?  Tabung and Giovannucci led another study, also using data from the thousands of participants in the Nurses’ Health Study and Health Professionals Follow-Up Study, to assess the “insulinemic potential” of diet and lifestyle – basically, how foods and exercise affect blood sugar and insulin resistance, as measured by certain biomarkers in the blood.  Foods that did not raise blood sugar or insulin resistance included wine, coffee, whole fruit, high-fat dairy (whole milk, sour cream, a half-cup of ice cream, a slice of cheese, etc.), nuts, and leafy green vegetables.  Physical activity was also good for lowering insulin resistance and blood sugar.

What do the experts make of this?  Benjamin Fu, a postdoctoral fellow in Lorelei Mucci’s lab at Harvard has been looking at these two different dietary patterns: “a diet associated with hyperinsulinemia, and a hyper-inflammation diet.”  The two diets have some overlaps, but are not identical.  Neither is good for men worried about prostate cancer, Mucci says, “particularly the hyper-insulinemia (blood sugar-raising) diet, which is associated with a 60-percent risk of more advanced or fatal prostate cancers.”  Let’s just let that sink in for a second:  if you eat a lot of carbs and sugar and you get prostate cancer, you’re more likely to have a serious form that could kill you.  Okay, let’s go on:

Mucci continues:  “The hyper-inflammatory diet also is associated with an increased risk of prostate cancer,” particularly in men who develop cancer at a younger age, in their forties and fifties.  “It may be that earlier-onset cancers are more susceptible to the effect of diet and lifestyle.”

What does heart health have to do with it?  A lot, for many reasons.  It turns out, says Mucci, that “cardiovascular disease and other chronic diseases are the major cause of death in many men who have prostate cancer.  If you look at men with localized prostate cancer and survival outcomes over 10 years, three-fourths of the deaths in those men will be due either to cardiovascular disease or another chronic disease.  Only one-fourth of the mortality is due to prostate cancer.”  Now, you may be thinking, we all have to die of something, right?  This is true, but “these men are dying sooner than they should, and eating a plant-based diet rich in cruciferous vegetables will help lower that risk of cardiovascular disease.”

Which brings us to the Mediterranean Diet:  Not only do people in Mediterranean countries, as compared to Americans, eat more vegetables and fruits, fewer fatty foods, less processed junk, and less red meat – “which increases insulin resistance, increases inflammation, raises cardiovascular risk and also is part of a dietary pattern that may increase obesity, as well,” as Mucci notes.  You know what else they eat a lot of?  Olive oil.  Greater than 30 ml a day, which is a little over two tablespoons.  “There’s really good evidence that extra virgin olive oil (EVOO), either on its own or as part of the Mediterranean diet, substantially lowers the risk of cardiovascular disease and lowers the risk of overall mortality.  The evidence specifically for men with prostate cancer is much more limited, but given the strong benefits for overall death and cardiovascular death in particular, not only using EVOO, but using it to replace butter or margarine, is something that is worth doing.”

 

Coming up:  Part 2:  What’s Good for the Prostate is Good for All of You!


In addition to the book, I have written much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

 

 ©Janet Farrar Worthington

 

 

 

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More Fuel for the 2020 Dumpster Fire: The Fallout of Not Screening for Prostate Cancer

The dumpster fire that is 2020 just keeps on burning, and the latest fuel for this crappy fire is a study, published in the Centers for Disease Control’s Morbidity and Mortality Weekly Report, showing that the incidence of men being diagnosed with metastatic prostate cancer doubled between 2003 and 2017. 

It doesn’t take a genius to figure out why:  Many men are not getting screened for prostate cancer.  It’s not just because of Covid.  (By the way, the coronavirus fallout is massive:  neglected routine medical maintenance – mammograms, colonoscopy, dental visits, yearly bloodwork, delayed care.  I am also extremely worried about the mental health ramifications of isolation, particularly on the elderly, which I will be addressing in other posts.)

No, this failure to screen for prostate cancer has been going on for a while.  It upsets me greatly, because I have known too many men over the years who have died from metastatic prostate cancer.  Wonderful men, like this one.  If these men had been screened regularly, with a simple PSA blood test even if they didn’t get a physical exam, they might have been diagnosed with cancer that was still confined to the prostate, cancer that’s much easier to treat, cancer that can be cured.

But no.  They didn’t get screened because their family doctor told them they didn’t need to.  And this is because, often, family doctors don’t know all the ins and outs of screening for particular cancers; they simply can’t be specialists in everything, so they rely heavily on the government guidelines.  They don’t consider that maybe the guidelines were written by people who might have an axe to grind, people who might want to ration care, people who might think that every single man diagnosed with prostate cancer gets unnecessary treatment and suffers terrible side effects, as if there hasn’t been any improvement in prostate cancer screening and treatment since the 1990s, or people who might believe, mistakenly, that prostate cancer is very slow-growing and doesn’t need to be treated at all – or all of the above.

In 2012, the brain trust of the U.S. Preventive Services Task Force (USPSTF) – speaking of dumpster fires– published guidelines discouraging routine screening for prostate cancer, concluding that the benefits do not outweigh the harms of treatment.  Urologists and medical oncologists protested this from the get-go.

How’d that work out for us?  Not great.  This was a disastrous ruling, and in 2018, the USPSTF walked it back, lamely, saying that prostate cancer screening for men aged 55-69 should be “an individualized decision based on personal preferences when weighing the benefits and harms of screening.”

What’s wrong with this?  So much.  For one thing, men need to start getting screened in their 40s.  If you have a family history of prostate cancer, you need to start getting screened at age 40.  For another, why is there a cutoff at age 69?  Healthy older men can still be diagnosed with prostate cancer, and can still be cured of it – or, conversely, still die from metastatic prostate cancer – so this, too, is just misguided.  I’ve written about that here.  For another, what are the personal preferences?  Not wanting to die of prostate cancer?

There are also lifestyle factors that put you at higher risk; do they mention those?  No.  If you are obese, or if you smoke, and you get prostate cancer, you are more likely to die of it.  (Good news:  if you lose weight and/or stop smoking, your risk of dying starts to drop right away.  You can read more about that here.)

And finally:  a lot of men don’t know their family history.  Or, their family history is happening in real time, as an uncle, father, brother, or grandfather is diagnosed with prostate cancer.  If you have prostate cancer in your family, that puts you at a higher risk of getting it, and you need to be screened regularly.

But what about the risks of treatment – namely, the risk of incontinence and impotence?  Fair question.  First, here’s something else very important you need to know:  Three-fourths of men in the U.S. are diagnosed with localized prostate cancer, and many of those men don’t have to do anything at all!  If you are diagnosed with Gleason 6 cancer, you can simply monitor it closely with active surveillance.  It may well be that the cancer will just sit there, not grow fast, and not spread.  You may never need treatment, and after many years, you can just die with it, not of it.   Or, you can get the cancer treated with surgery or radiation.

But about those risks:  Yes, there are side effects to surgery.  This is why you do your best to minimize those side effects by finding the best surgeon possible.  Here are some ways to do that.  Those side effects are treatable.  There are much worse side effects to treatment for metastatic prostate cancer, which includes androgen deprivation therapy (ADT).  ADT’s side effects include the loss of testosterone, loss of sexual desire, weight gain, loss of muscle mass, breast enlargement, and a higher risk of other health problems including diabetes, heart attack, stroke, metabolic syndrome, osteoporosis, and cognitive impairment.

I know men with metastatic prostate cancer who would give anything to be dealing with the aftereffects of surgery for localized prostate cancer if it meant they could be cancer-free.  

Hear this:  I am confident the survival rates for men with metastatic prostate cancer are rising and will go up even higher with the use of second-line hormonal therapy (androgen receptor blockers like abiraterone, enzalutamide, and others); with smarter use of SBRT radiation to treat isolated spots of cancer before widespread metastasis; with immunotherapy and gene-targeted therapy, which are both still in their early days in prostate cancer; and with PSMA-targeted radionuclides.  There are many exciting treatments in the works, and some of them have the potential to be game-changers.

That said, for the years this study covered (between 2003-2017), fewer than one-third of men diagnosed with metastatic prostate cancer survived five years.  The five-year survival rate actually rose during the study’s time period, from nearly 29 percent between 2001 and 2005 to more than 32 percent between 2011 and 2016.  Again, don’t let these numbers discourage you:  they are going to get better with the new treatments on the horizon.

In contrast, for men diagnosed with localized prostate cancer, the 10-year relative survival rate was 100 percent.

Between 2003 and 2017, about 3.1 million men were diagnosed with prostate cancer.  In 2003, 78 percent of these men were diagnosed with localized cancer; in 2017, this had dropped to 70 percent.  In 2003, 4 percent of men were diagnosed with metastatic prostate cancer.  By 2017, this percentage had doubled to 8 percent.

If you’ve read this blog for a while, you may remember that I wrote about this disturbing trend in 2018.  You can read more about it here.  I interviewed Edward “Ted” Schaeffer, M.D., Ph.D., Chairman of Urology at Northwestern University.  Here’s some of what he said:  “Hindsight is 20/20, and there’s no question that when PSA screening first became available, many men were overdiagnosed.”  Back in the 1990s, doctors hadn’t figured out who needs to be treated and who can safely do active surveillance.  They know a lot more now.  In 2018, Schaeffer had already noticed this disturbing trend – declining rates in the diagnosis of low-grade, localized prostate cancer, and a sharp increase in the number of men newly diagnosed with metastatic prostate cancer.  “We need nationwide refinements in prostate cancer screening and treatment, to prevent men from being diagnosed with metastatic prostate cancer.

“We don’t want to diagnose low-grade cancers,” which may never need to be treated.  “But we really need to pick up the disease before it becomes metastatic.”

 

In addition to the book, I have written much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

 

 ©Janet Farrar Worthington

 

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Could Anti-Inflammatory Drugs Work Against Prostate Cancer?

If, as we have seen, inflammation can lead to prostate cancer, could anti-inflammatory agents help protect against it?

The jury’s still out.  However:  Johns Hopkins epidemiologist Elizabeth Platz, Sc.D., has been intrigued by this possibility for many years.  She is senior author of a new study on the use of aspirin and statins, published in Cancer Prevention Research.  The study, of men in the placebo arm of the Prostate Cancer Prevention Trial, doesn’t answer this question once and for all – but adds more weight to the idea that, for lowering the risk of developing potentially fatal prostate cancer, fighting inflammation is a good thing.

Evidence from observational studies has suggested that when taken regularly over time, aspirin may lower the risk of prostate cancer.  These drugs block enzymes that play a key role in the body’s inflammatory response.  Other studies have linked long-term use of statins, prescription drugs that are used to lower cholesterol but that also are anti-inflammatory, to a lower risk of advanced and metastatic prostate cancer.

In this most recent study, the investigators looked for inflammation markers in benign prostate tissue samples.  “We compared the use aspirin and statins with the presence and extent of inflammation in the prostate tissue,” says Platz.  They also looked at prostate biopsy slides for the presence of certain immune cells that are involved in inflammation.

“Of 357 men, 61 percent reported aspirin use, and 32 percent reported statin use,” Platz continues.  “Aspirin users were more likely to have low FoxP3, a T regulatory cell marker, and statin users were more likely to have a low CD68, a macrophage marker.”  “Our results suggest these medications may alter the immune environment of the prostate. A next step is to determine whether these immune alterations may underlie the epidemiologic observations that taking an aspirin or statin may protect against getting advanced prostate cancer, and dying from it.”

Prostate Cancer Loves Fats          

Here’s some more recent research out of Johns Hopkins, a neat bit of  basic science that may help explain the findings of Platz’s recent study:  “Our work is mechanistic,” says investigator Marikki Laiho, M.D., Ph.D., director of the Division of Molecular Radiation Sciences, “and provides insight into how the tumor microenvironment senses the excess load of the lipids.  Diet and statins obviously relate to the amount and regulation of the lipids, and have shown those clear correlations to prostate cancer.  However, we need to understand why to be able to correct the problem. Our work provides at least one explanation how the lipids fuel cancer. One part of the work was just to feed the prostate cancer cells with cholesterol, which made them more invasive.”

It turns out that even on a cellular level, prostate cancer gravitates to its own kind of junk food – the tiny version of deep-fried Oreos with a side of chili cheese fries.  Laiho and colleagues have just figured out how the body enables prostate cancer’s terrible diet.

The culprit is a lipid-regulating protein called CAVIN1, the scientists reported in the journal, Molecular Cancer Research.  In lab studies, when CAVIN1 was removed from cells in and around the prostate tumor, the fatty acid that was in those cells spilled into the tumor’s microenvironment.   The effect on prostate cancer cells was dramatic:  the cancer cells soaked up the lipids, which then acted as turbo fuel to make the cancer spread more aggressively.

“In every prostate cancer cell line we tested,” says research fellow Jin-Yih Low, Ph.D., the study’s first author, “tumor cells universally had an appetite for the lipids, using them to strengthen the protective membrane around the cell, synthesize proteins and make testosterone to support and fuel the cancer’s growth.  The tumor cells then behaved more aggressively, exhibiting invasive and metastatic behavior.  Just having access to the lipids gave the tumor cells more power; the tumor’s behavior changed.”

But wait!  There’s more:  nearby cells changed, too.  Deprived of their lipids, normal stromal cells started to churn out inflammatory molecules, adding fuel of their own to the fire. 

Laiho’s team then confirmed their findings in mouse models, comparing tumors with and without CAVIN1 in the stromal cells.  In the mice, Laiho says, “although the presence or absence of CAVIN1 did not affect the speed of tumor growth, lack of CAVIN1 definitely caused the cancer to spread.  All of the mice with tumors that lacked CAVIN1 had a twofold to fivefold increase in metastasis.  The tumors also had a fortyfold to hundredfold increase in lipids and inflammatory cells.”

The investigators were surprised at these results, Laiho adds.  “We suspected CAVIN1 was important, but we didn’t realize how important.  The tumor’s microenvironment matters, and the amount of lipids matters a lot.”  Just changing the level of lipids “created a situation of rampant metastasis.”

What could come from this research?  One possibility is development of a new biomarker:  a loss of CAVIN1 in local or locally advanced cancer, for example, could signal a higher risk of metastasis.  The next step is to understand more about the inflammatory process in the tumor’s microenvironment.  “We want to understand why the inflammation brings in macrophages, immune cells that further exacerbate the inflammatory process, instead of T cells, which should attack the cancer.”  The more scientists know about how inflammation does its nasty work to inflame cancer, the closer we are to finding a way to stop it.

 

In addition to the book, I have written about this story and much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org.  The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask.  I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease.  Many doctors don’t do this, so it’s up to you to ask for it.

©Janet Farrar Worthington

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Infection, Inflammation, and Prostate Cancer

Why does it matter if you eat right and exercise?  Everybody knows the answer; in fact, we’ve all heard it so many times, it’s easy to tune it out:  diet and exercise are good for you.  Duh!  Who’s going to argue with that? Having a healthy lifestyle is right up there with world peace as a worthy goal!

Bear with me here:  With a topic such as this, I know I’m either preaching to the choir – people who are already exercising and eating a pretty good diet – or I run the risk of turning off the people I really want to hear this message, by seeming to preach at all: people who might think, “Go ahead, tell me what to do.  I really enjoy that.  Micromanage my life.  Maybe you’d like to come over and look at my closet and tell me what shirt to wear today.”

Okay, fine!  I’m not here to tell you what to do.  But I am going to try really hard to tell you why you might want to do certain things, and how good diet and exercise – or the lack thereof – can affect prostate cancer.

Please pardon the long set-up, but let’s begin with some facts, with plenty of links for further reading:

If you exercise, you are less likely to have cancer return after treatment, less likely to get metastatic prostate cancer and die of it.  What does exercise do?  A lot of good things for your vascular system, which, in turn, can help slow down prostate cancer metastasis.  But you know what it also does?  It helps you lose weight.

And it just so happens, men who lose weight are less likely to die of prostate cancer.

And sugar can make cancers grow faster.

And men who stop smoking are less likely to have cancer come back after treatment, and less likely to die of prostate cancer.

Exercise also helps control stress, and the stress hormone, cortisol, affects adrenal receptors, and can play a role in making cancer grow and spread faster.

Now, here’s why all this matters so much:  smoking, not exercising, quaffing sugary drinks, eating processed, fatty foods, and being overweight all contribute to inflammation.

I’m going to be writing a lot about inflammation in the next few posts, because it is becoming increasingly evident that inflammation can lead to cancer – and it’s quite possible that if we can prevent inflammation, we may prevent or at least slow down cancer.

What Inflammation Does

In a landmark study, Karen Sfanos, Ph.D., and scientists at Johns Hopkins have shown for the first time that bacterial infection can cause prostate cancer.  The study was led by Sfanos and her former graduate student, Eva Shrestha, Ph.D., in collaboration with Angelo De Marzo, M.D., Ph.D., Jonathan Coulter, Ph.D., and colleagues.  Infection? That’s not the same as inflammation!  True… but bear with me.

The bacterial culprit found in this study belongs to the family Enterobacteriaceae, which includes E. coli. Better known as a nasty gastrointestinal bug, E. coli causes inflammation in the urinary tract and is a known cause of bacterial prostatitis.  As the scientists discovered, colibactin, a genotoxin produced by some strains of E. coli, can also instigate a series of unfortunate events in the prostate.  Bacterial infection leads to acute and chronic inflammation, which can lead to the development of a lesion in the prostate called proliferative inflammatory atrophy (PIA), first described by pathologist De Marzo, oncologist William (Bill) Nelson, M.D., Ph.D., and other Johns Hopkins scientists; it can also cause DNA damage. The presence of colibactin is even more ominous, because it can directly lead to double-stranded DNA breakage. 

Sfanos suspects that this combination leads, in turn, to another development:  fusion of two genes, TMPRSS2 and ERG, that normally should remain separate, but in this case get abnormally spliced together.  Now, it may be that by themselves, TMPRSS2 and ERG are like Robert Leroy Parker and Harry Alonzo Longabaugh:  put them together, and they became Butch Cassidy and the Sundance Kid, and together, they got into much worse trouble than either one managed alone.  This TMPRSS2/ERG fusion – found in as many as half of all prostate cancers – is thought be an early event leading to the development of prostate cancer.

“We found evidence in human tissues (from prostatectomy specimens) that bacterial infections are initiating the TMPRSS2/ERG fusion,” says Sfanos.  “We don’t think this is the only way bacterial infections contribute to cause prostate cancer.  But in this particular study, the way we looked at it was by tracking the presence of these TMPRSS2/ERG fusions.”

It is entirely possible, notes De Marzo, “that other types of mutations or events could also be caused by bacterial infections or inflammation.  But looking at these fusions gave us ‘smoking gun’ evidence that bacterial infection was the initiating event.”  Sfanos adds that “the colibactin-producing bacteria, TMPRSS2/ERG fusions, PIA, and tiny buds of cancer were all there, in the same place at the same time, a snapshot of prostate cancer being born.”  The team’s early findings are available online in BioRxiv, a scientific data-sharing website, and a manuscript for publication is undergoing peer review.

Bacterial infection is a known cause of other cancers.  H. pylori, for example, is a well-established cause of stomach cancer.  “We believe that many different types of microorganisms, certain types of sexually transmitted infections (STIs), and other infections in the prostate can certainly cause the same chain of events,” says Sfanos.

How did the bacteria get into the prostate?  They could have come from the urethra.  “These bacteria are good crawlers,” Sfanos says.  De Marzo recalls what the late Don Coffey, Ph.D., the longtime director of the Brady’s scientific labs, used to say: “The urethra is like the Holland Tunnel for bacteria.”

Note:  These tiny cancers are not the cancers that were biopsied and that led to the diagnosis of prostate cancer; they’re too young even to achieve a Gleason grade.  They’re just baby sites of cancer cropping up, in addition to the more mature cancer that was already there.  Prostate cancer is multifocal:  in most men with prostate cancer, several sites of cancer develop at the same time.  But because of the unique molecular tools used in this study – looking for TMPRSS2/ERG fusions and “ERG-positive PIA” – Sfanos, De Marzo and colleagues were able to catch the formation of these invasive cancers in real time.  “This might start to explain the multifocal nature of prostate cancer,” says Sfanos. “There might be multiple infections or other inflammatory events that occur throughout a man’s lifetime.”

Sfanos suspects that the men whose tissue was used for this study “likely all had undiagnosed infections.”  These findings may lead to development of a new test, using urine or prostatic fluid, to look for colibactin or markers of inflammation in the prostate.  Future studies may look at urine samples along with prostate tissue for such markers, and  new imaging technology may one day be able to detect inflammation, as well.

For more than 20 years, De Marzo and Sfanos, with Brady scientists Bill Nelson, Srinivasan Yegnasubramanin, M.D. Ph.D., Elizabeth Platz, Sc.D., and William Isaacs, Ph.D., have studied inflammation as a risk factor for prostate cancer, particularly looking at PIA.  Sfanos “has also been the major champion of infection” as a risk factor, De Marzo says.  Now, these two paths of investigation have come together.

Could dietary changes make a difference?  “Bill Nelson showed years ago that loss of expression of the GSTP1 gene rendered prostate cells more susceptible to DNA damage caused by a chemical compound that is found in charred meat,” says De Marzo.  “Infection plus a bad diet might make this worse, and then combine that with the underlying genetics.  There might be multiple culprits, a constellation of things over years.”  We’re going to look more at diet in future posts.

Coming up next:  Could anti-inflammatory drugs help?

 

In addition to the book, I have written about this story and much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org.  The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask.  I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease.  Many doctors don’t do this, so it’s up to you to ask for it.

©Janet Farrar Worthington

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